# Protein palmitoylation in synuclein pathophysiology

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $198,720

## Abstract

PROJECT SUMMARY
This proposal presents a five-year research career development program focused on the potential role of
dysregulated palmitoylation, modification of proteins by the fatty acid palmitate, in the vesicle trafficking defects
caused by α-synuclein (αSyn) in Parkinson’s disease (PD). The research and training plan is based upon the
candidate’s prior experience in molecular neuroscience, the experienced mentorship of Dr. Dennis Selkoe, and
the full institutional support of Brigham and Women’s Hospital (BWH). Completion of the plan is expected to
result in important insights into PD biology in addition to the candidate’s career development to an independent
laboratory-based investigator.
The current lack of disease-modifying therapies for PD, the second most common neurodegenerative disorder,
is a large unmet need. The causative role of the neuronal protein αSyn is well appreciated, since mutations in
the αSyn gene cause PD and aggregates of αSyn are found in Lewy Bodies, the pathological hallmark of PD.
Many studies now suggest that αSyn-dependent disruption of vesicular trafficking plays an important role in the
pathogenesis of PD. The proposed research tests the hypothesis that αSyn, which binds to membranes via an
amphipathic helix, inhibits palmitoylation of SNARE and SNARE-related proteins, thus disrupting their function
in vesicle fusion. Accordingly, the aims are 1) to determine whether a set of SNARE and SNARE-related
proteins with PD relevance is dysregulated in animal and iPSC-based models of PD; 2) to determine if
enhancement of palmitoylation reduces vesicle accumulation caused by pathologic αSyn; and 3) to determine
if enhancement of palmitoylation ameliorates PD-like phenotypes in a mouse model.
The career development plan is designed to support the candidate’s goal of becoming an independent
investigator with both clinical training in movement disorders and scientific expertise in membrane-protein
interactions and vesicle trafficking in human synucleinopathies. Critical to the plan is the unparalleled
mentorship of Dr. Selkoe, who has decades of experience in guiding scientists and physician scientists to
leadership positions in academia. Formal didactics and seminars on techniques, ethics, and professional skills,
combined with an eminent advisory committee add further structure to the career development plan. Finally,
the collaborative environment of the Ann Romney Center for Neurologic Diseases at BWH provides numerous
material and human resources readily available to the candidate. Taken together, these elements help ensure
attainment of the candidate’s goals upon completion of the proposal.

## Key facts

- **NIH application ID:** 9889191
- **Project number:** 5K08NS110876-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Gary P. H. Ho
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,720
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889191

## Citation

> US National Institutes of Health, RePORTER application 9889191, Protein palmitoylation in synuclein pathophysiology (5K08NS110876-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889191. Licensed CC0.

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